PROJECT ABSTRACT Over the past 50 years, the US smoking rate was reduced by two-thirds from 42% in the 1960s to 14% currently. Smoking prevention campaigns, such as those led by the Center for Tobacco Products, include multimedia educational programs and health warning labels on cigarette packaging, which are highly effective and played a key role in this reduction. However, smoking rates remain high in certain vulnerable subpopulations (e.g. youth, minorities, LGBTQ people) and the CTP is now targeting smoking prevention campaigns to these subpopulations. One vulnerable subpopulation that has not yet been targeted is people with serious mental illnesses (SMIs) such as bipolar disorder (BD), schizophrenia (SCZ), and major depressive disorder (MDD). SMIs affect more than 1 in 5 Americans and people with SMIs are twice as likely to smoke as people without SMIs. Accordingly 40% of all cigarettes are smoked by people with SMIs. Education campaigns have long been used to reach people with SMIs and have been successful in increasing treatment rates and reducing suicidal behavior. In light of their success, the lack of a smoking prevention campaign targeted to the SMI subpopulation is striking. The first step in designing a successful campaign is establishing the scientific foundation for messaging that will resonate with the SMI subpopulation. Focusing on the mental health consequences of smoking is a logical choice. People with SMIs typically spend 15%-25% of their lives symptomatic, and symptoms are distressing, cause role impairment, and when severe require hospitalization. We will conduct the most rigorous investigation yet done on whether smoking is a risk factor for greater psychiatric symptom severity in people with SMIs, using three specific aims: SA1: Determine whether smoking is a risk factor for increased time in illness episodes in people with SMIs. We hypothesize that BD smokers will spend more time in mood episodes (depression+mania) than BD non-smokers, SCZ smokers will spend more time in psychotic episodes, and MDD smokers will spend more time in depressive episodes. SA2: Determine whether smoking is a risk factor for increased time in depression across SMIs. Depression is the psychiatric syndrome most commonly attributed to smoking, and people with BD, SCZ, and MDD are all vulnerable to depression. An alternate hypothesis to SA1 is that smoking has a specific depressogenic effect and that across all three SMIs smokers will spend more time in depressive episodes than non-smokers. SA3: Determine predictors of within-person changes in smoking behavior (initiating, quitting, relapsing). We hypothesize that smokers with lower psychiatric symptom severity will be more likely to quit smoking, while quitters who experience a subsequent increase in symptoms will be more likely to relapse into smoking. The proposed project will advance tobacco regulatory science and protect public health by establishing the scientific foundation for a smoking prevention campaign targeted to people with SMIs - arguably the vulnerable subpopulation most harmed by smoking.